Partial and whole gene deletion mutations of the GCK and HNF1A genes in maturity-onset diabetes of the young

• Published in: Diabetologia Vol. 50; no. 11; pp. 2313 - 2317
• Main Authors: Ellard, S, Thomas, K, Edghill, E. L, Owens, M, Ambye, L, Cropper, J, Little, J, Strachan, M, Stride, A, Ersoy, B, Eiberg, H, Pedersen, O, Shepherd, M. H, Hansen, T, Harries, L. W, Hattersley, A. T
• Format: Journal Article
• Language: English
• Published: Berlin Berlin/Heidelberg : Springer-Verlag 01-11-2007; Springer; Springer Nature B.V
• Subjects: Adolescent; Adult; Age of Onset; Biological and medical sciences; Child, Preschool; Cysts; Deletion mutation; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - genetics; Diabetes. Impaired glucose tolerance; DNA probes; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Exons; Female; GCK; Gene Deletion; Gene dosage; Genes; Genetics; Genotype & phenotype; Glucokinase; Glucokinase - deficiency; Glucokinase - genetics; Hepatocyte nuclear factor 1; Hepatocyte Nuclear Factor 1-alpha - deficiency; Hepatocyte Nuclear Factor 1-alpha - genetics; Hepatocyte nuclear factor 4; HNF-1α; HNF-4α; HNF1A; HNF1B; HNF4A; Humans; Male; Medical sciences; MODY; Mutation; noninsulin-dependent diabetes mellitus; Oligonucleotides; Pedigree; Phenotype; Sequence analysis; TCF1; Transcription factors; United Kingdom > UK; Denmark; Endocrinopathy; HNF-4α; HNF-1α; Diabetes mellitus; HNF1B; HNF1A; Deletion mutation; GCK; MODY; Maturity-onset diabetes of the young; Gene; HNF4A; Deletion; Mutation; TCF1
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-007-0798-6

Aims/hypothesis Heterozygous mutations of glucokinase (GCK) and hepatocyte nuclear factor-1 alpha (HNF1A; also known as hepatic transcription factor 1 [TCF1]) genes are the most common cause of MODY. Genomic deletions of the HNF1B (also known as TCF2) gene have recently been shown to account for one third of mutations causing renal cysts and diabetes syndrome. We investigated the prevalence of partial and whole gene deletions in UK patients meeting clinical criteria for GCK or HNF-1α/-4α MODY and in whom no mutation had been identified by sequence analysis. Methods A multiplex ligation-dependent probe amplification (MLPA) assay was developed using synthetic oligonucleotide probes for 30 exons of the GCK, HNF1A and HNF4A genes. Results Partial or whole gene deletions were identified in 1/29 (3.5%) probands using the GCK MLPA assay and 4/60 (6.7%) of probands using the HNF1A/-4A MLPA assay. Four different deletions were detected: GCK exon 2, HNF1A exon 1, HNF1A exons 2 to 10 and HNF1A exons 1 to 10. An additional Danish pedigree with evidence of linkage to HNF1A had a deletion of exons 2 to 10. Testing other family members confirmed co-segregation of the deletion mutations with diabetes in the pedigrees. Conclusions/interpretation Large deletions encompassing whole exons can cause GCK or HNF-1α MODY and will not be detected by sequencing. Gene dosage assays, such as MLPA, are a useful adjunct to sequence analysis when a diagnosis of MODY is strongly suspected.